Hepatic encephalopathy (HE) is a serious neuropsychiatric and neurocognitive complication in acute and chronic liver disease. HE is a significant and increasing health care problem due to the large and increasing prevalence of chronic liver disease. HE is characterized by impairments of the sleep-wake cycle, cognition, memory, learning, motor coordination, consciousness, decreased energy levels and personality change, ranging from minimal HE (MHE) to overt HE (OHE). MHE is manifested with cognitive impairment and has detrimental effects on health related quality of life and the ability to perform complex tasks such as driving. In addition, OHE is clinically manifested with mental and motor disorders and the symptoms ranges from disorientation through sedation and coma.
Naturally occurring steroids are subject to intense metabolism and are typically not suitable for oral administration. The metabolites of the endogenous steroid hormones pregnenolone, progesterone, deoxycorticosterone, cortisone and cortisol, known as pregnanolones as well as the metabolites of testosterone, androstenedione and dehydroepiandrosterone, have all been the subject of various studies, at least partially elucidating their role in the neurological signal system in mammals. The steroid metabolites induce CNS symptoms and disorders and steroids act as positive modulators on the gamma-aminobutyric acid receptor-chloride ionophore (GABAA-R) complex and are therefore called GABAA receptor modulating steroids (GAMS).
Certain steroids have been shown to be specific GABAA receptor enhancers. Examples of these steroids can inter alia be found in WO 2008/063128. Some of these steroids are potent and have e.g. been shown to have an ability to induce amnesia, sedation and anesthesia in pharmacological dose. WO 99/45931 and WO 03/059357 disclose antagonistic effects of steroids. Wang et al. 2000 (Acta Physiol Scand 169, 333-341) and Wang et al. 2002 (J Neurosci 22(9):3366-75) disclose antagonistic effects of 3β-OH-5α-pregnan-20-one and other 3β-OH-5α/β pregnan steroids. WO2006/056794 and WO2010/144498 discloses use of compounds for treatment of liver decompensation, hepatic encephalopathy and portal hypertension. There is a need to provide new and effective therapeutic treatments for hepatic encephalopathy and related disorders